PROJECT SUMMARY Kv3-family potassium channels regualte rapid firing in auditory neurons and in many other parts of the nervous system, including the cerebral cortex. Functional channels may comprise homomers of a single Kv3- family subunit or heteromers of two different subunits. One of these subunits, Kv3.4, is usually expressed at low levels in the mature nervous system but has been found to undergo a major increase at the onset of Alzheimer's disease in humans, as well as in an animal model of this disease. In common with the Kv3.3 subunit, with which it forms heteromers, Kv3.4 interacts with cellular proteins that regulate cell fate and metabolism. Specifically, Kv3.4-containing channels bind two proteins two proteins closely associated with Alzheimer's disease, Protocadherin 9 (PCDH9) and BAG2. The former, PCDH9, is a cell adhesion molecule, while BAG proteins are co-chaperones that are required for the rapid turnover of phosphorylated Tau protein. Accumulation of phosphorylated Tau protein is one of the major hallmarks of Alzheimer's disease. The experiments in the supplemental application will use biochemical, electrophysiological and immunological approaches to determine whether the presence of Kv3-family channels containing Kv3.3 and/or Kv3.4 alters the functions of PCDH9 and BAG proteins. Specifically, they will test whether the accumulation of phosphorylated Tau protein is altered by the presence or activation of these channels. The finding of a positive interaction could provide new therapeutic targets for the treatment of Alzheimer's disease.